Your browser doesn't support javascript.
loading
Mostrar: 20 | 50 | 100
Resultados 1 - 10 de 10
Filtrar
1.
Am J Hum Genet ; 99(3): 711-719, 2016 09 01.
Artículo en Inglés | MEDLINE | ID: mdl-27545680

RESUMEN

The overall understanding of the molecular etiologies of intellectual disability (ID) and developmental delay (DD) is increasing as next-generation sequencing technologies identify genetic variants in individuals with such disorders. However, detailed analyses conclusively confirming these variants, as well as the underlying molecular mechanisms explaining the diseases, are often lacking. Here, we report on an ID syndrome caused by de novo heterozygous loss-of-function (LoF) mutations in SON. The syndrome is characterized by ID and/or DD, malformations of the cerebral cortex, epilepsy, vision problems, musculoskeletal abnormalities, and congenital malformations. Knockdown of son in zebrafish resulted in severe malformation of the spine, brain, and eyes. Importantly, analyses of RNA from affected individuals revealed that genes critical for neuronal migration and cortex organization (TUBG1, FLNA, PNKP, WDR62, PSMD3, and HDAC6) and metabolism (PCK2, PFKL, IDH2, ACY1, and ADA) are significantly downregulated because of the accumulation of mis-spliced transcripts resulting from erroneous SON-mediated RNA splicing. Our data highlight SON as a master regulator governing neurodevelopment and demonstrate the importance of SON-mediated RNA splicing in human development.


Asunto(s)
Encéfalo/embriología , Encéfalo/metabolismo , Proteínas de Unión al ADN/genética , Genes Esenciales/genética , Discapacidad Intelectual/genética , Antígenos de Histocompatibilidad Menor/genética , Mutación/genética , Empalme del ARN/genética , Animales , Encéfalo/anomalías , Encéfalo/patología , Proteínas de Unión al ADN/análisis , Proteínas de Unión al ADN/metabolismo , Discapacidades del Desarrollo/genética , Discapacidades del Desarrollo/patología , Discapacidades del Desarrollo/fisiopatología , Anomalías del Ojo/genética , Femenino , Haploinsuficiencia/genética , Cabeza/anomalías , Heterocigoto , Humanos , Discapacidad Intelectual/patología , Discapacidad Intelectual/fisiopatología , Masculino , Enfermedades Metabólicas/genética , Enfermedades Metabólicas/metabolismo , Antígenos de Histocompatibilidad Menor/análisis , Antígenos de Histocompatibilidad Menor/metabolismo , Linaje , ARN Mensajero/análisis , Columna Vertebral/anomalías , Síndrome , Pez Cebra/anomalías , Pez Cebra/embriología , Pez Cebra/genética
2.
Hum Genet ; 135(12): 1399-1409, 2016 12.
Artículo en Inglés | MEDLINE | ID: mdl-27681385

RESUMEN

Intellectual disabilities are genetically heterogeneous and can be associated with congenital anomalies. Using whole-exome sequencing (WES), we identified five different de novo missense variants in the protein phosphatase-1 catalytic subunit beta (PPP1CB) gene in eight unrelated individuals who share an overlapping phenotype of dysmorphic features, macrocephaly, developmental delay or intellectual disability (ID), congenital heart disease, short stature, and skeletal and connective tissue abnormalities. Protein phosphatase-1 (PP1) is a serine/threonine-specific protein phosphatase involved in the dephosphorylation of a variety of proteins. The PPP1CB gene encodes a PP1 subunit that regulates the level of protein phosphorylation. All five altered amino acids we observed are highly conserved among the PP1 subunit family, and all are predicted to disrupt PP1 subunit binding and impair dephosphorylation. Our data suggest that our heterozygous de novo PPP1CB pathogenic variants are associated with syndromic intellectual disability.


Asunto(s)
Estudios de Asociación Genética , Cardiopatías Congénitas/genética , Discapacidad Intelectual/genética , Proteína Fosfatasa 1/genética , Adolescente , Adulto , Niño , Preescolar , Exoma/genética , Femenino , Predisposición Genética a la Enfermedad , Cardiopatías Congénitas/fisiopatología , Humanos , Discapacidad Intelectual/fisiopatología , Masculino , Mutación Missense , Fosforilación/genética
3.
Cleft Palate Craniofac J ; 50(2): 158-67, 2013 Mar.
Artículo en Inglés | MEDLINE | ID: mdl-22315960

RESUMEN

Objective : Reconstructive surgery to improve psychological well-being is commonly offered to children with craniofacial conditions. Few studies have explored the challenges of reconstructive surgery beyond the physical risks: poor treatment outcomes, infection, brain damage, and death. This qualitative study aims to understand the psychological and social implications such interventions can have for individuals with craniofacial conditions. Design : A total of 38 individuals between the ages of 12 and 61 with such craniofacial conditions as Sturge-Weber syndrome, Treacher Collins syndrome, Möbius syndrome, cleft lip and palate, Noonan syndrome, Crouzon syndrome, and amniotic band syndrome participated in semistructured video-recorded interviews. Participants were recruited at conferences, through study flyers, and by word of mouth. Descriptive, thematic analysis was used to identify themes related to reconstructive surgery. Results : Dominant themes included undergoing surgery to reduce stigmatization, the psychological and social implications of the interventions, outcome satisfaction, parental involvement in decision making about surgery, and recommendations for parents considering surgery for their children with craniofacial conditions. Experiences with reconstructive surgery varied, with some participants expressing surgical benefits and others, disillusionment. Conclusions : The range of participant attitudes and experiences reflect the complexity of reconstructive surgery. Pediatric health care teams involved in the care of children with craniofacial conditions play an important role in advising patients (and their parents) about existing treatment options. The psychological and social implications of reconstructive surgery should be relayed to help families weigh the risks and benefits of surgery in an informed and meaningful way.


Asunto(s)
Labio Leporino , Padres , Labio Leporino/cirugía , Fisura del Paladar/cirugía , Disostosis Craneofacial , Humanos , Disostosis Mandibulofacial , Padres/psicología , Procedimientos de Cirugía Plástica
4.
Mil Med ; 187(Suppl 1): 36-39, 2021 12 30.
Artículo en Inglés | MEDLINE | ID: mdl-34967403

RESUMEN

Genetic counseling for military beneficiaries poses unique challenges and counseling opportunities. In order to fully meet the needs of this population, genetic counseling involves critical ethical and psychosocial considerations. This article reviews some elements of genetic counseling that must be considered when working with beneficiaries in the military health system.


Asunto(s)
Asesoramiento Genético , Personal Militar , Consejo , Humanos , Personal Militar/psicología
5.
Mol Genet Genomic Med ; 7(2): e00483, 2019 02.
Artículo en Inglés | MEDLINE | ID: mdl-30415494

RESUMEN

BACKGROUND: Genomic sequencing has become a widely used tool in clinical and research settings in both civilian and military healthcare systems. METHODS: In this paper, we consider potential military-specific implications of returning genomic sequencing secondary findings to ensure the proper protections, policies, and processes are in place for the use of this information. RESULTS: We specifically use two examples to highlight potential military implications of the return of secondary findings. CONCLUSION: Clinicians and researchers are strongly encouraged to consider the military implications of the return of results for informed consent of service members or their families undergoing clinical or research genomic sequencing.


Asunto(s)
Displasia Ventricular Derecha Arritmogénica/genética , Tamización de Portadores Genéticos/normas , Asesoramiento Genético/normas , Hallazgos Incidentales , Hipertermia Maligna/genética , Medicina Militar/normas , Personal Militar , Secuenciación Completa del Genoma/normas , Humanos , Consentimiento Informado
SELECCIÓN DE REFERENCIAS
DETALLE DE LA BÚSQUEDA